Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors

Mitochondrial DNA (mtDNA) mutations scattered through coding and noncoding regions have been reported in cancer. The mechanisms that generate such mut ations and the importance of mtDNA mutations in tumor development are still not clear. Here we present the identification of a specific and highly pol ymorphic homopolymeric C stretch (D310), located within the displacement (D ) loop, as a mutational hotspot in primary tumors. Twenty-two % of the 247 primary tumors analyzed harbored somatic deletions/insertions at this monon ucleotide repeat. Moreover, these alterations were also present in head and neck preneoplastic lesions. We further characterized the D310 variants tha t appeared in the lung and head and neck tumors. Most of the somatic altera tions found in tumors showed deletion/insertions of 1- or 2-bp generating D 310 variants identical to constitutive polymorphisms described previously. Sequencing analysis of individual clones from lymphocytes revealed that pat ients with D310 mutations in the tumors had statistically significant highe r levels of D310 heteroplasmy (more than one length variant) in the lymphoc yte mtDNA as compared with the patients without D310 mutations in the tumor mtDNA. On the basis of our observations, we propose a model in which D310 alterations are already present in normal cells and achieve homoplasmy in t he tumor through a restriction/amplification event attributable to random g enetic drift and clonal expansion.